Although an onset mechanism of Alzheimer dementia has not yet been fully elucidated, it is thought that toxicity to neuronal cells of aggregates of Aβ molecules may play an important role. A matter of aggregates formation of Aβ molecules is a matter of conformation of Aβ molecules.
Aβ molecules are degradation products produced by cleavage of neuronal amyloid precursor proteins with e.g. β secretase and include two variants, i.e. Aβ1-40 and Aβ1-42 (hereinafter referred to as “Aβ42”). Among the two variants, it is reported that Aβ42 is more likely to aggregate and is more correlated with diseases and neurotoxicity than Aβ1-40. Also, localization of microglias and astrocytes in Aβ plaques present in the brain is observed and is suggested to correlate with neurotoxicity.
It is hypothesized that accumulation of Aβ, when viewed from different angle, may be an aging process of individuals and hence, when accumulation of Aβ exceeds its threshold value as a consequence of loss of balance in clearance, onset of disease results. Based on these hypotheses, there have been attempts to develop a small molecular size inhibitor to β secretase involved in cleavage of the precursor protein so as to inhibit the Aβ production per se. However, a mechanism of Aβ production is not so plain and the results obtained heretofore are not necessarily satisfactory.
On the other hand, a report by B. Solomon et al. (see Non-patent reference 1) for in vitro inhibition of Aβ aggregation with an anti-Aβ antibody, an antibody to the N-terminal of Aβ, and a report by Schenk et al. (see Non-patent reference 2) that administration of Aβ42 prior to aggregation in admixture with adjuvant to mice reduced deposition of cerebral amyloids, had opened up a road to a new immunotherapy. In fact, a vaccine therapy for Alzheimer dementia with Aβ has been attempted to prove its efficacy to some extent, such as reduction in deposition of cerebral amyloids (see Non-patent references 3 and 4). However, while efficacy may be observed with a vaccine therapy, serious detrimental side effects may also be seen due to induction of inflammatory reactions by activation of T cells and thus a vaccine therapy has not yet been established as a safe and efficacious approach for the prophylaxis and treatment of the disease.
It is presumed that efficacy of an Aβ vaccine therapy may be due to localized, activated microglia cells that take in via Fc receptor and decompose deposited Aβ antigen-antibody complex and that may bind to a soluble Aβ to prevent local deposition.
On the other hand, McLaurin et al. demonstrated that passive immunity with an antibody to Aβ4-10, a terminal portion of Aβ molecule, could effectively inhibit or delay onset of disease in experiments performed in mice (see Non-patent reference 5). In case of passive immunity for transfer of an antibody, induction of an inflammatory reaction due to activation of T cells is unlikely to occur but as little as 0.1% or less of anti-Aβ antibodies in serum may pass through the blood-brain barrier to thereby necessitate frequent administration of a large amount.    Non-patent reference 1: Solomon, B. et al., (1996) Pro. Natl. Acad. Sci., 93, 452-455    Non-patent reference 2: Schenk, D. et al., (1999) Nature, 400, 173    Non-patent reference 3: Nicoll, J. A. et al., (2003) Nature Medicine, 9, 448    Non-patent reference 4: Monsonego, A. et al., (2003) Science, 302, 834-838    Non-patent reference 5: McLaurin et al., (2002) Nature Medicine, 8, 1263-1269